Based on a proposed mechanism of action of nerve growth factor (NGF) that involves complexation with plasma membrane receptors, internalization by endocytosis followed by retrograde axonal transport, and interaction with nuclear receptors to directly effect specific transcriptional events, it is proposed to examine the individual steps of NGF function and the structural features of the molecule responsible for them. Isolation and characterization of guinea pig NGF, including sequence analysis and x-ray diffraction studies, will be performed as well as sequence analysis of human NGF. Structural analyses of the alpha and gamma subunit and the 7S complex will be continued. Proteolytic fragments of mouse beta NGF will be generated and tested for activity in a variety of assays. The plasma membrane receptor of superior cervical neurons will be purified to homogeneity and antibodies raised to it. The nuclear receptors of the same tissues will also be isolated after photoaffinity labelling with the 4-azidobenzoyl derivative of mouse beta-NGF. Receptor regulation will be studied in both superior cervical and dorsal root ganglia neurons. The receptors present in the synaptosomes of central nervous system neurons will be examined in a similar fashion. The role of NGF in medullary carcinoma of the thyroid and idiopathic orthostatic hypertension will be studied.